Developmental immunotoxicity of chemicals in rodents and its possible regulatory impact

Abstract

Around 25% of the children in developed countries are affected with immune-based diseases. Juvenile onset diseases such as allergic, inflammatory and autoimmune diseases have shown increasing prevalences in the last decades. The role of chemical exposures in these phenomena is unclear. It is thought that the developmental immune system is more susceptible to toxicants than the mature situation. Developmental immunotoxicity (DIT) testing is nowadays not or minimally included in regulatory toxicology requirements. We reviewed whether developmental immune parameters in rodents would provide relatively sensitive endpoints of toxicity, whose inclusion in regulatory toxicity testing might improve hazard identification and risk assessment of chemicals. For each of the nine reviewed toxicants, the developing immune system was found to be at least as sensitive or more sensitive than the general (developmental) toxicity parameters. Functional immune (antigen-challenged) parameters appear more affected than structural (non-challenged) immune parameters. Especially, antibody responses to immune challenges with keyhole limpet hemocyanine or sheep red blood cells and delayed-type hypersensitivity responses appear to provide sensitive parameters of developmental immune toxicity. Comparison with current tolerable daily intakes (TDI) and their underlying overall no observed adverse effect levels showed that for some of the compounds reviewed, the TDI may need reconsideration based on developmental immune parameters. From these data, it can be concluded that the developing immune system is very sensitive to the disruption of toxicants independent of study design. Consideration of including functional DIT parameters in current hazard identification guidelines and wider application of relevant study protocols is warranted.

Keywords:

• allergy
• developmental immunotoxicity
• DOTC
• DEHP
• Ethanol
• EOGRTS
• immune system
• juvenile
• MeHg
• OECD 443
• rat

Declaration of interest

The authors are affiliated to the National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. RIVM is a government agency under the Dutch Ministry of Health, Welfare and Sports. RIVM has fully sponsored the present piece of work. The design of the appraisal, the conduct of the appraisal and the conclusions drawn in the paper are the exclusive work product of the authors and may not necessarily be those of their employer, RIVM.